rs144346996

chr17-81934652-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong

The NM_006907.4(PYCR1):c.633+1G>C variant causes a splice donor change. The variant allele was found at a frequency of 0.0000326 in 1,564,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

PYCR1
NM_006907.4 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.00

Variant links:

Genes affected

PYCR1 (HGNC:9721): (pyrroline-5-carboxylate reductase 1) This gene encodes an enzyme that catalyzes the NAD(P)H-dependent conversion of pyrroline-5-carboxylate to proline. This enzyme may also play a physiologic role in the generation of NADP(+) in some cell types. The protein forms a homopolymer and localizes to the mitochondrion. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

PYCR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.09583333 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.4, offset of 24, new splice context is: ctgGTgggg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-81934652-C-G is Pathogenic according to our data. Variant chr17-81934652-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 325904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYCR1	NM_006907.4 linkuse as main transcript	c.633+1G>C		splice_donor_variant		ENST00000329875.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYCR1	ENST00000329875.13 linkuse as main transcript	c.633+1G>C		splice_donor_variant		1	NM_006907.4	P1	P32322-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000287

AC:

AN:

174502

Hom.:

AF XY:

0.0000214

AC XY:

AN XY:

93388

show subpopulations

Gnomad AFR exome

AF:

0.000102

Gnomad AMR exome

AF:

0.0000744

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000280

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1412472

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

698244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000531

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000331

Gnomad4 OTH exome

AF:

0.0000342

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.000231

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000170

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2023	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 30450527, 19648921) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	This sequence change affects a donor splice site in intron 5 of the PYCR1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PYCR1 are known to be pathogenic (PMID: 19648921). This variant is present in population databases (rs144346996, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with Cutis laxa (PMID: 19648921, 30450527). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 325904). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2016

- -

Cutis laxa

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The PYCR1 c.633+1G>C variant occurs in a canonical splice site (donor) and is reported in one study in two unrelated individuals with cutis laxa, including one in a homozygous state and one in a compound heterozygous state (Reversade et al. 2012). The c.633+1G>C variant is reported at a frequency of 0.000048 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence and the potential impact of splice donor variants, the c.633+1G>C variant is classified as likely pathogenic for cutis laxa, recessive. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Wiedemann-Rautenstrauch-like progeroid syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.23

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

0.86

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

D;D;D;D;D

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.28

Position offset: -23

DS_DL_spliceai

0.99

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over